ABSTRACT Immune activation and inflammation persist despite combination antiretroviral therapy (cART) for HIV. This chronic inflammation contributes to greater HIV-associated cardiometabolic morbidity and mortality. Our group recently found that a specific molecular mechanism - the tryptophan-kynurenine (TRP-KYN) pathway - is disrupted in HIV and associated with atherosclerosis progression. The TRP-KYN pathway is of potential importance in both HIV and sleep/circadian regulation because HIV Tat protein and inflammatory molecules induce TRP-KYN pathway activation, which results in a degradation of TRP, an imbalance and accumulation of KYN and its downstream metabolites, and a reduction in melatonin, which is a circadian regulator with anti- inflammatory properties. Sleep and circadian disruption are highly prevalent in HIV, and sleep and circadian disruption are well-recognized to increase inflammation. Therefore, sleep and circadian disruption may further activate the TRP-KYN pathway, increasing HIV-associated cardiometabolic disease risk. The objective of this application is to investigate the TRP-KYN pathway as a molecular mechanism by which sleep and circadian disruption increase risk for HIV-associated cardiometabolic disease. We will also investigate the reciprocal relationship by which HIV-related TRP-KYN pathway activation may feed back to increase sleep and circadian disruption. Our multidisciplinary team will leverage the ongoing multi-site Women's Interagency HIV Study (WIHS) cohort of well-characterized HIV+ and demographically similar HIV- women, which has extensive cardiometabolic data. Our pilot data from WIHS indicate that (1) sleep and circadian disruption is prevalent in the WIHS cohort, (2) sleep and circadian disruption can potentiate immune activation, particularly in HIV- infected individuals, and (3) TRP-KYN pathway activation increases risk for cardiometabolic disease. Thus, we will study 240 women (120 HIV+ aviremic, 120 HIV-, 40-70 y) in a longitudinal study design, assessing sleep and circadian disruption, TRP-KYN pathway activation and cardiometabolic risk yearly over 2 years (3 time points). Aim 1 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, TRP-KYN pathway activation in HIV+ women. Aim 2 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, HIV-associated cardiometabolic disease risk. Aim 3 is to determine whether the TRP-KYN pathway is a mechanism that links sleep and circadian disruption to an increase in HIV-associated cardiometabolic disease risk. No studies to date have examined TRP-KYN pathway activation and its metabolites as a mechanism linking sleep/circadian disruption to HIV-related comorbidities such as cardiometabolic disease. Results will provide novel insights into the mechanistic relationships between sleep and circadian disruption, TRP-KYN pathway activation, and HIV-associated cardiometabolic disease risk and provide a strong foundation upon which to test targeted sleep and circadian interventions to reduce risk for cardiometabolic disease in women with HIV.